Neuroprotective effects of vitamin D in an Alzheimer's disease rat model: Improvement of mitochondrial dysfunction via calcium/calmodulin-dependent protein kinase kinase 2 activation of Sirtuin1 phosphorylation.

Mitochondrial dysfunction is an early event in Alzheimer's disease (AD) pathogenesis. To assess the impact of vitamin D3 (Vit.D) on neurogenesis, we investigated its role in mitigating cognitive impairment and mitochondrial dysfunction through calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)-mediated phosphorylation of Sirtuin1 (SIRT1) in an aluminum-chloride-D-galactose (AlCl3-D-gal)-induced AD rat model. Rats were distributed into four groups: control, AlCl3 + D-gal (10 + 60 mg/kg, ip), Vit.D (500 IU/kg, po), and AlCl3 + D-gal+Vit.D. Novel object recognition (NOR), Morris Water Maze, and passive avoidance (PA) tests were used to measure memory abilities. The hippocampal tissue was used to assess vitamin D3 receptor (VDR) and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α) expression by quantitative real-time polymerase chain reaction (qRT-PCR), CAMKK2, p-SIRT1, phosphorylated-AMP-activated protein kinase (p-AMPK), dynamin-related-protein-1 (Drp1), and mitofusin-1 (Mnf1) proteins by western blot and Ca2+ levels, endothelial nitic oxide synthase (eNOS), superoxide dismutase (SOD), amyloid beta (Aß), and phospho tau (p-Tau) via enzyme-linked immunosorbent assay(ELISA) in addition to histological and ultrastructural examination of rat's brain tissue. Vit.D-attenuated hippocampal injury reversed the cognitive decline and Aß aggregation, and elevated p-Tau levels in the AlCl3 + D-gal-induced AD rat model. In AlCl3 + D-gal-exposed rats, Vit.D induced VDR expression, normalized Ca2+ levels, elevated CAMKK2, p-AMPK, p-SIRT1, and PGC-1α expression. Vit.D reduced Drp1, induced Mnf1, increased mitochondrial membrane potential, preserved mitochondrial structure, restored normal mitochondrial function, and retained normal eNOS level and SOD activity in AlCl3 + D-gal rats. In conclusion, our findings proved that Vit.D may ameliorate cognitive deficits in AlCl3 + D-gal-induced AD by restoring normal mitochondrial function and reducing inflammatory and oxidative stress via CAMKK2-AMPK/SIRT1 pathway upregulation.

Addressing Peroxisome Proliferator-Activated Receptor-gamma in 3-Nitropropionic Acid-Induced Striatal Neurotoxicity in Rats.

Telmisartan (TEL) is an angiotensin II type 1 receptor blocker and a partial activator of peroxisome proliferator-activated receptor-gamma (PPARγ), which regulates inflammatory and apoptotic pathways. Increasing evidence has demonstrated the PPARγ agonistic property of TEL in several brain disorders. This study aims to explore the neuroprotective impact of TEL in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats. The PPARγ effect of TEL was affirmed by using the PPARγ agonist pioglitazone (PIO), and the antagonist GW9662. 3-NP led to a significant reduction in body weight alongside motor and cognitive functioning. The striata of the 3-NP-treated rats showed energy-deficit, microglia-mediated inflammatory reactions, apoptotic damage as well as histopathological lesions. PIO and TEL improved motor and cognitive perturbations induced by 3-NP, as confirmed by striatal histopathological examination, energy restoration, and neuronal preservation. Both drugs improved mitochondrial biogenesis evidenced by elevated mRNA expression of PPARγ, PGC-1α, and TFAM, alongside increased striatal ATP and SDH. The mitochondrial effect of TEL was beyond PPARγ activation. As well, their anti-inflammatory effect was attributed to suppression of microglial activation, and protein expression of pS536 p65 NF-κB with marked attenuation of striatal inflammatory mediator's release. Anti-inflammatory cytokine IL-10 expression was concurrently increased. TEL effectively participated in neuronal survival as it promoted phosphorylation of Akt/GSK-3ß, further increased Bcl-2 expression, and inhibited cleavage of caspase-3. Interestingly, co-treatment with GW9662 partially revoked the beneficial effects of TEL. These findings recommend that TEL improves motor and cognitive performance, while reducing neuronal inflammation and apoptosis in 3-NP-induced neurotoxicity via a PPARγ-dependent mechanism.

Inhibition of boldenone-induced aggression in rats by curcumin: Targeting TLR4/MyD88/TRAF-6/NF-κB pathway.

The illicit abuse of anabolic steroids is associated with brutal aggression, which represents a serious health hazard and social threat. Boldenone is commonly used for doping by athletes and adolescents for esthetic purposes and to enhance performance and endurance during competitions. However, the mechanistic pathways underlying boldenone-induced behavioral deviations and neuronal toxicity have not yet been elucidated. On the other hand, the natural polyphenol curcumin is appreciated for its relative safety, potent antioxidant activity, and anti-inflammatory properties. Therefore, the present study was initiated to explore the signaling pathways underlying boldenone-induced anxiety and aggression in rats, and the protective effects of curcumin. To achieve this aim, male Wistar albino rats were randomly distributed into control, curcumin (100 mg/kg in sesame oil, p.o., once daily), boldenone (5 mg/kg, intramuscular, once weekly), and combination groups. Rats were challenged across the open field, irritability, defensive aggression, and resident-intruder tests. The prefrontal cortex was used to assess serotonin level, oxidative stress markers, and mRNA expression of myeloid differentiation primary response gene (MyD88), TNFR-associated factor 6 (TRAF-6), tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), protein expression of toll-like receptor 4 (TLR4), and phosphorylated nuclear factor-κB transcription factor (NF-κB p65). Unprecedented, the current results showed that boldenone elicited aggression in rats accompanied by depleted serotonin, enhanced oxidative stress, and exaggerated inflammatory response via upregulation of TLR4/MyD88/TRAF-6/NF-κB pathway. Interestingly, curcumin mitigated boldenone-induced neurobehavioral disturbances in rats, normalized the oxidant/antioxidant balance, and suppressed TLR4/MyD88/TRAF-6/NF-κB pathway and its downstream proinflammatory signaling molecules TNF-α and IL-1ß.

Nano-ivabradine averts behavioral anomalies in Huntington's disease rat model via modulating Rhes/m-tor pathway.

Huntington's disease (HD) is characterized by abnormal involuntary movements together with cognitive impairment and disrupted mood changes. 3-nitropropionic acid (3-NP) is one of the chemo-toxic models used to address the striatal neurotoxicity pattern encountered in HD. This study aims to explain the neuroprotective effect of nano-formulated ivabradine (nano IVA) in enhancing behavioral changes related to 3-NP model and to identify the involvement of ras homolog enriched striatum (Rhes)/mammalian target of rapamycin (m-Tor) mediated autophagy pathway. Rats were divided into 6 groups, the first 3 groups received saline (control), ivabradine (IVA), nano IVA respectively, the fourth received a daily dose of 3-NP (20 mg/kg, s.c) for 2 weeks, the fifth received 3-NP + IVA (1 mg/kg, into the tail vein, every other day for 1 week) and the last group received 3-NP + nano IVA (1 mg/kg, i.v, every other day for 1 week). Interestingly, nano IVA reversed motor disabilities, improved memory function and overcame the psychiatric changes. It boosted expression of autophagy markers combined with down regulation of Rhes, m-Tor and b-cell lymphoma 2 protein levels. Also, it restored the normal level of neurotransmitters and myocardial function related-proteins. Histopathological examination revealed a preserved striatal structure with decreased number of darkly-degenerated neurons. In conclusion, the outcomes of this study provide a well-recognized clue for the promising neuroprotective effect of IVA and the implication of autophagy and Rhes/m-Tor pathways in the 3-NP induced HD and highlight the fact that nano formulations of IVA would be an auspicious approach in HD therapy.

Mechanistic insights into the protective effects of chlorogenic acid against indomethacin-induced gastric ulcer in rats: Modulation of the cross talk between autophagy and apoptosis signaling.

BACKGROUND: This study aimed to investigate the gastroprotective effect of chlorogenic acid (CGA) against Indomethacin (IND)-induced gastric ulcer (GU) in rats and its underlying mechanism, especially through autophagic and apoptotic pathways. METHODS: Seventy-five rats were divided into five groups; control, IND (50 mg/kg, p.o.), CGA (100 mg/kg, p.o., 14 days), IND pretreated with CGA (50 mg/kg or 100 mg/kg, p.o., 14 days). The stomach tissues were examined to calculate the ulcer index and analyze markers of autophagy (beclin-1, LC3-II/LC3-I and p62), lysosomal function (cathepsin-D) and apoptosis (Bcl-2, Bax and caspase-3), along with expression of Akt/mTOR pathway using western blot or ELISA techniques. In addition, viability of gastric mucosal cells was detected by flowcytometry. Structural changes were assessed histologically, while autophagic and apoptotic changes of gastric mucosa were observed by transmission electron microscopy. RESULTS: CGA exhibited a dose-dependent gastroprotective effect by reversing IND-induced accumulation of autophagic vacuoles, significant reduction in beclin-1, LC3-II/LC3-I, and p62 levels, and down-regulation of p-Akt/p-mTOR expression. CGA100 also restored normal autolysosomal function by modulation of cathepsin-D levels. Furthermore, pretreatment with CGA100 was significantly associated with an increase in antiapoptotic protein Bcl-2 along with a decrease in proapoptotic Bax and caspase-3 proteins in such a way that impairs IND-induced apoptosis. This was confirmed by CGA-induced significant decrease in annexin V+ cells. CONCLUSIONS: The natural compound CGA offers a novel gastroprotective intervention against IND-induced GU through restoration of normal autophagic flux, impairment of apoptosis in a crosstalk mechanism mediated by Akt/mTOR pathway reactivation, and alleviation of IND-induced lysosomal dysfunction.

Liraglutide mends cognitive impairment by averting Notch signaling pathway overexpression in a rat model of polycystic ovary syndrome.

AIMS: Polycystic ovary syndrome (PCOS), the rifest endocrine disorder in women, is involved in disrupting many metabolic processes. However, the impact of PCOS on cognitive deficits is still uncertain. Recently, Notch signaling pathway was identified as a key modifier in regulating the pathological process in the ovary and various neurodegenerative disorders. Liraglutide has favourable neuroprotective effects that may protect against the possible cognitive dysfunction in PCOS. MAIN METHODS: PCOS was induced in rats by administrating Letrozole orally for 21 successive days. Then, Liraglutide (LIR) was administered intraperitoneally for 30 days. Memory was examined using Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests. Western blotting, enzyme immunoassay, and quantitative real-time PCR were used to examine Notch signaling downstream targets, as well as assessing the expression of the components of various pathways cross talked with Notch signaling in memory impairment. Furthermore, histopathological examination was performed to examine neuronal changes. KEY FINDINGS: Notch signaling was overexpressed in PCOS rats, which increased Aß aggregation, apoptosis, and neuroinflammation. Additionally, histopathological examination showed neuronal degeneration, which was marked by diminished acetylcholine levels in the PCOS rats' hippocampi. Finally, serum levels of insulin and testosterone were elevated while estradiol was reduced. Treatment with LIR repaired Notch signaling-attributed changes and improved the PCOS-induced memory impairment in rats. SIGNIFICANCE: The obtained findings confirm that Notch signaling activation in the hippocampus of rats impairs cognitive functions in PCOS, which is mitigated by LIR. Therefore, LIR may offer a novel therapeutic intervention to impede PCOS-induced dementia.

Acetyl-11-keto-ß-boswellic acid prevents testicular torsion/detorsion injury in rats by modulating 5-LOX/LTB4 and p38-MAPK/JNK/Bax/Caspase-3 pathways.

AIMS: Testicular torsion/detorsion (T/D) is a critical medical condition that necessitates prompt surgical intervention to avoid testicular atrophy and infertility. The use of natural compounds may protect against the associated detrimental oxidative stress and inflammatory responses. Interestingly, acetyl-11-keto-ß-boswellic acid (AKBA), the main active constituent of Boswellia resin, has shown potent inhibitory effect on 5-lipoxygenase enzyme which converts arachidonic acid into inflammatory mediators. Therefore, this study was conducted to assess the protective mechanisms by which AKBA may protect against testicular T/D injury in rats. MAIN METHODS: Male rats were randomly distributed into five groups: Sham, AKBA (50 mg/kg, p.o.), unilateral testicular T/D, AKBA at two dose levels (25 or 50 mg/kg for 15 successive days) followed by T/D. Histological examination and Johnsen's score were performed to assess testicular injury and perturbations in spermatogenesis. Biochemical parameters included markers of testicular function (serum testosterone), oxidant/antioxidant status (malondialdehyde, glutathione), inflammation (5-lipoxygenase, leukotriene-B4, myeloperoxidase, interleukin-1ß, interleukin-6), apoptosis (Bax, Bcl2, caspase-3), DNA integrity (quantitative DNA fragmentation, DNA laddering, PARP-1), energy production (ATP), in addition to p38 MAPK and JNK protein expression. KEY FINDINGS: In a dose dependent manner, AKBA significantly inhibited testicular T/D-induced upregulation of 5-LOX/LTB4 and p38-MAPK/JNK/Bax pathways and their associated downstream inflammatory and apoptotic cascades. These effects were accompanied with ATP replenishment and DNA preservation, resulting ultimately in salvage of the testis. SIGNIFICANCE: Unprecedentedly, the present mechanistic study revealed the pathways by which AKBA may inhibit testicular T/D injury and offered a novel protective approach that may attenuate the severity of this condition.

Carvedilol attenuates l-arginine induced acute pancreatitis in rats through modulation of oxidative stress and inflammatory mediators.

Acute pancreatitis (AP) is a sudden pancreatic inflammation accompanied by an excessive reactive oxygen species production that provokes inflammation. The present study investigated whether carvedilol can protect against l-arginine induced AP in a rat model and studied the mechanisms associated with its protection. Rats were divided into four groups: a control group, an AP group (injected with 2 doses of l-arginine 250 mg/100 g body weight at 1 h interval, intraperitoneally) on the 22nd day of the experiment, a carvedilol group (10 mg/kg, orally) for 21 successive days, and finally a carvedilol + AP group. It was found that pretreatment with carvedilol decreased α-amylase and lipase activities as well as C-reactive protein (CRP) and malondialdehyde levels; on the other hand, it improved the reduced glutathione (GSH) level and catalase (CAT) activity. In addition, carvedilol markedly decreased all of the following biomarkers: nuclear factor kappa B (NF-κB p65), p38 mitogen-activated protein kinases (P38-MAPK), signal transducer and activator of transcription 1 (STAT1-α), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), myeloperoxidase (MPO), and phospholipase A2 (PLA2) levels that was induced by l-arginine. Finally, carvedilol noticeably down regulated the pancreatitis associated protein (PAP2) and the pancreas platelets activating factor (PAF) genes expression. In conclusion: carvedilol protected against l-arginine induced AP in rats, via the inhibition of cellular oxidative stress and inflammatory pathways that contributed to pancreas injury.

Lansoprazole enhances the antidiabetic effect of dapagliflozin in fortified diet-fed streptozotocin-treated diabetic rats.

Dapagliflozin (DAPA) is used for treating type 2 diabetes, whereas lansoprazole (LPZ) is used as a traditional antiulcer drug. The present study investigated the possible antidiabetic effects of LPZ on fortified diet-fed streptozotocin (FDF/STZ)-induced insulin-resistant diabetic rats. On the basis of the current results, it can be concluded that LPZ could be used as an add-on drug along with the conventional treatment for T2D as it showed beneficial effects in the current experimental model of insulin resistance.

Protective effects of febuxostat against paraquat-induced lung toxicity in rats: Impact on RAGE/PI3K/Akt pathway and downstream inflammatory cascades.

AIMS: The herbicide paraquat causes fatal lung toxicity by induction of xanthine oxidase, production of free radicals and inflammation. Febuxostat, a xanthine oxidase inhibitor and anti-gout has recently shown anti-inflammatory activity. Accordingly, this study was carried out to investigate whether febuxostat may attenuate paraquat-induced lung toxicity and to explore the possible underlying mechanisms. MAIN METHODS: Rats were administered either vehicle, a single dose of paraquat (30 mg/kg, i.p.), febuxostat (15 mg/kg, oral), or both for 14 successive days. Serum LDH and sRAGE were estimated. Lung tissue xanthine oxidase activity, SOD, TAC, MDA, and RAGE, HMGB1 gene expression, PI3K/Akt and ß-catenin protein expression, MMP-9, IL-8, VEGF and COX-2 gene expression were estimated. KEY FINDINGS: Results showed that paraquat induced lung injury characterized by enhanced oxidative stress and inflammation, upregulated RAGE, HMGB1 gene expression, PI3K/Akt and ß-catenin protein expression. Administration of febuxostat inhibited the deleterious effects of paraquat on lung through inhibition of xanthine oxidase activity and related oxidative stress, downregulation of RAGE/PI3K/Akt pathway, and suppression of ß-catenin protein expression and its downstream inflammatory mediators. SIGNIFICANCE: The present study showed that febuxostat may abrogate paraquat-induced lung toxicity and demonstrated a novel mechanism for its ameliorative effects.

Montelukast attenuates rotenone-induced microglial activation/p38 MAPK expression in rats: Possible role of its antioxidant, anti-inflammatory and antiapoptotic effects.

Montelukast (MK),a cysteinyl leukotriene (CysLT1) receptor antagonist, latterly exhibited a remarkable neuroprotective activity in various neurodegenerative disorders. This study aims to elucidate the neuroprotective effect of MK in rotenone-induced Parkinson's disease(PD) model in rats. Ninety six male rats were split into four groups: vehicle control (0.2 ml/kg/48 h, sc), MK (10 mg/kg/day, ip), rotenone (1.5 mg/kg/48 h, sc.) and rotenone pretreated with MK. Rotenone treatment led to significant reduction in motor functioning and elevation in oxidative stress markers. Additionally, upregulation of p38 mitogen-activated protein kinase (p38 MAPK) and CysLT1 receptor expressions were anchored with enhanced striatal microglial activation generating a severe neuro-inflammatory milieu. Furthermore, an augmentation in p53 expression and cleaved caspases-3 activity increased apoptotic neurodegeneration synchronized with reduction of striatal tyrosine hydroxylase (TH) content. Changes in neuronal morphology was also noted. MK administration significantly mitigated motor impairment and rise in oxidative stress mediators. As well, the anti-inflammatory activity of MK was manifested by hindering the principal controller of inflammatory pathway, nuclear factor-kappa B, followed by its downstream pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta), by attenuating striatal microglial activation and hampering the expression of both p38 MAPK and CysLT1. Moreover, MK revealed a decline in p53 expression with its downstream cleaved caspases-3 which resulted in preservation of striatal TH terminals as verified by increased striatal TH content and improvement in the histopathological changes incited by rotenone. In conclusion, MK endowed neuroprotective effects in rotenone-induced PD animal model via attenuation of microglial cell activation and p38 MAPK expression.

Lipoic acid and pentoxifylline mitigate nandrolone decanoate-induced neurobehavioral perturbations in rats via re-balance of brain neurotransmitters, up-regulation of Nrf2/HO-1 pathway, and down-regulation of TNFR1 expression.

Behavioral perturbations associated with nandrolone decanoate abuse by athletes and adolescents may be attributed to oxidative stress and inflammation. However, the underlying mechanisms are not yet fully explored. On the other hand, the natural antioxidant lipoic acid can pass the blood brain barrier and enhance Nrf2/HO-1 (nuclear factor erythroid-2 related factor 2/heme oxygenase-1) pathway. In addition, the phosphodiesterase-IV inhibitor xanthine derivative pentoxifylline has a remarkable inhibitory effect on tumor necrosis factor-alpha (TNF-α). Therefore, this study aimed at investigation of the possible protective effects of lipoic acid and/or pentoxifylline against nandrolone-induced neurobehavioral alterations in rats. Accordingly, male albino rats were randomly distributed into seven groups and treated with either vehicle, nandrolone (15mg/kg, every third day, s.c.), lipoic acid (100mg/kg/day, p.o.), pentoxifylline (200mg/kg/day, i.p.), or nandrolone with lipoic acid and/or pentoxifylline. Rats were challenged in the open field, rewarded T-maze, Morris water maze, and resident-intruder aggression behavioral tests. The present findings showed that nandrolone induced hyperlocomotion, anxiety, memory impairment, and aggression in rats. These behavioral abnormalities were accompanied by several biochemical changes, including altered levels of brain monoamines, GABA, and acetylcholine, enhanced levels of malondialdehyde and TNF-α, elevated activity of acetylcholinesterase, and up-regulated expression of TNF-α receptor-1 (TNFR1). In addition, inhibited catalase activity, down-regulated Nrf2/HO-1 pathway, and suppressed acetylcholine receptor expression were observed. Lipoic acid and pentoxifylline combination significantly mitigated all the previously mentioned deleterious effects mainly via up-regulation of Nrf2/HO-1 pathway, inhibition of TNF-α and down-regulation of TNFR1 expression. In conclusion, the biochemical and histopathological findings of this study revealed the protective mechanisms of lipoic acid and pentoxifylline against nandrolone-induced behavioral changes and neurotoxicity in rats.

Attenuating effects of coenzyme Q10 and amlodipine in ulcerative colitis model in rats.

CONTEXT: Ulcerative colitis is a chronic inflammatory bowel disease. Recent studies reported a pivotal role of elevated intracellular calcium in this disorder. Coenzyme Q10 (CoQ10) and amlodipine are known to maintain cellular energy, decrease intracellular calcium concentration in addition to their antioxidant and anti-inflammatory properties. OBJECTIVE: The aim of this study was to evaluate the possible protective effects of CoQ10, amlodipine and their combination on ulcerative colitis. MATERIALS AND METHODS: Colitis was induced in rats by intracolonic injection of 3% acetic acid. CoQ10 (10 mg/kg), amlodipine (3 mg/kg) and their combination were administered for 8 consecutive days before induction of colitis. RESULTS: Our results showed that administration of CoQ10, amlodipine and their combination decreased colon tissue malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), prostaglandin E2 (PGE2), myeloperoxidase (MPO) and heat shock protein (HSP70) levels induced by intracolonic injection of acetic acid and restored many of the colon structure in histological examination. On the other hand, they increased superoxide dismutase (SOD) activity, adenosine-5'-triphosphate (ATP) and interleukin-10 (IL-10) colonic contents. DISCUSSION AND CONCLUSION: Administration of either CoQ10 or amlodipine was found to protect against acetic acid-induced colitis. Moreover, their combination was more effective than individual administration of either of them. The protective effect of CoQ10 and amlodipine may be in part via their antioxidant, anti-inflammatory and energy restoration properties.

Amelioration of nandrolone decanoate-induced testicular and sperm toxicity in rats by taurine: effects on steroidogenesis, redox and inflammatory cascades, and intrinsic apoptotic pathway.

The wide abuse of the anabolic steroid nandrolone decanoate by athletes and adolescents for enhancement of sporting performance and physical appearance may be associated with testicular toxicity and infertility. On the other hand, taurine; a free ß-amino acid with remarkable antioxidant activity, is used in taurine-enriched beverages to boost the muscular power of athletes. Therefore, the purpose of this study was to investigate the mechanisms of the possible protective effects of taurine on nandrolone decanoate-induced testicular and sperm toxicity in rats. To achieve this aim, male Wistar rats were randomly distributed into four groups and administered either vehicle, nandrolone decanoate (10mg/kg/week, I.M.), taurine (100mg/kg/day, p.o.) or combination of taurine and nandrolone decanoate, for 8 successive weeks. Results of the present study showed that taurine reversed nandrolone decanoate-induced perturbations in sperm characteristics, normalized serum testosterone level, and restored the activities of the key steroidogenic enzymes; 3ß-HSD, and 17ß-HSD. Moreover, taurine prevented nandrolone decanoate-induced testicular toxicity and DNA damage by virtue of its antioxidant, anti-inflammatory, and anti-apoptotic effects. This was evidenced by taurine-induced modulation of testicular LDH-x activity, redox markers (MDA, NO, GSH contents, and SOD activity), inflammatory indices (TNF-α, ICAM-1 levels, and MMP-9 gene expression), intrinsic apoptotic pathway (cytochrome c gene expression and caspase-3 content), and oxidative DNA damage markers (8-OHdG level and comet assay). In conclusion, at the biochemical and histological levels, taurine attenuated nandrolone decanoate-induced poor sperm quality and testicular toxicity in rats.

Attenuation of renal ischemia/reperfusion injury by açaí extract preconditioning in a rat model.

AIMS: Renal ischemia/reperfusion (I/R) injury is highly associated with morbidity and mortality. Oxidative stress, inflammation, and apoptosis play pivotal roles in the development of renal dysfunction following renal I/R. Experimental studies have reported the effectiveness of many antioxidant and anti-inflammatory compounds against renal I/R injury. On the other hand, açaí (Euterpe oleracea Mart. Palmae, Arecaceae) has recently gained considerable appreciation as a natural source of antioxidants. However, the effect of açaí extract has not been studied before on renal I/R. Therefore, the present study was carried out to investigate the possible mechanisms of renal injury attenuation by açaí extract in a rat renal I/R model. MAIN METHODS: To achieve the aim of the study, rats were administered açaí extract at two dose levels (500 and 1000 mg/kg) for 15 consecutive days before bilateral renal I/R induction. Serum and kidneys were isolated and used for subsequent biochemical analysis. KEY FINDINGS: The present data showed that açai extract significantly and dose-dependently attenuated I/R-induced renal damage. It suppressed the levels of blood urea nitrogen (BUN), serum creatinine, and renal tissue content of kidney injury molecule-1 (KIM-1). In addition, it inhibited serum lactate dehydrogenase (LDH) activity. Moreover, renal contents of malondialdehyde (MDA), myeloperoxidase (MPO), interferon-gamma (IFN-γ), caspase-3, collagen IV, and endothelin-1 were reduced, while renal interleukin-10 (IL-10) content was increased by açaí extract administration to rats before renal I/R induction. SIGNIFICANCE: Açaí extract ameliorated bilateral I/R-induced renal injury in rats in a dose-dependent manner.

Pomegranate extract protects against cerebral ischemia/reperfusion injury and preserves brain DNA integrity in rats.

AIM: Interruption to blood flow causes ischemia and infarction of brain tissues with consequent neuronal damage and brain dysfunction. Pomegranate extract is well tolerated, and safely consumed all over the world. Interestingly, pomegranate extract has shown remarkable antioxidant and anti-inflammatory effects in experimental models. Many investigators consider natural extracts as novel therapies for neurodegenerative disorders. Therefore, this study was carried out to investigate the protective effects of standardized pomegranate extract against cerebral ischemia/reperfusion-induced brain injury in rats. MAIN METHODS: Adult male albino rats were randomly divided into sham-operated control group, ischemia/reperfusion (I/R) group, and two other groups that received standardized pomegranate extract at two dose levels (250, 500 mg/kg) for 15 days prior to ischemia/reperfusion (PMG250+I/R, and PMG500+I/R groups). After I/R or sham operation, all rats were sacrificed and brains were harvested for subsequent biochemical analysis. KEY FINDINGS: Results showed reduction in brain contents of MDA (malondialdehyde), and NO (nitric oxide), in addition to enhancement of SOD (superoxide dismutase), GPX (glutathione peroxidase), and GRD (glutathione reductase) activities in rats treated with pomegranate extract prior to cerebral I/R. Moreover, pomegranate extract decreased brain levels of NF-κB p65 (nuclear factor kappa B p65), TNF-α (tumor necrosis factor-alpha), caspase-3 and increased brain levels of IL-10 (interleukin-10), and cerebral ATP (adenosine triphosphate) production. Comet assay showed less brain DNA (deoxyribonucleic acid) damage in rats protected with pomegranate extract. SIGNIFICANCE: The present study showed, for the first time, that pre-administration of pomegranate extract to rats, can offer a significant dose-dependent neuroprotective activity against cerebral I/R brain injury and DNA damage via antioxidant, anti-inflammatory, anti-apoptotic and ATP-replenishing effects.

Melatonin protects against diazinon-induced neurobehavioral changes in rats.

Diazinon is an organophosphorous pesticide with a prominent toxicity on many body organs. Multiple mechanisms contribute to diazinon-induced deleterious effects. Inhibition of acetyl-cholinesterase, cholinergic hyperstimulation, and formation of reactive oxygen species may play a role. On the other hand, melatonin is a pineal hormone with a well-known potent antioxidant activity and a remarkable modulatory effect on many behavioral processes. The present study revealed that oral diazinon administration (25 mg/kg) increased anxiety behavior in rats subjected to elevated plus maze and open-field tests possibly via the induction of changes in brain monoamines levels (dopamine, norepinephrine, and serotonin). Additionally, brain lipid peroxides measured as malondialdehyde (MDA) and tumor necrosis factor alpha (TNF-α) levels were elevated, while the activity of brain glutathione peroxidase enzyme was reduced by diazinon. Co-administration of oral melatonin (10 mg/kg) significantly attenuated the anxiogenic activity of diazinon, rebalanced brain monoamines levels, decreased brain MDA and TNF-α levels, and increased the activity of brain glutathione peroxidase enzyme.